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IPEX is caused by mutations in the gene FOXP3, which encodes the transcription factor forkhead box P3 (FOXP3). FOXP3 is widely considered to be the master regulator of the regulatory T cell lineage.[7][8] FOXP3 mutations lead to the dysfunction of CD4+ regulatory T cells. In healthy people, regulatory T cells maintain immune homeostasis.[9] When there is a FOXP3 mutation, regulatory T cells do not function properly and cause autoimmunity.[10][11]
IPEX onset usually happens in infancy. If left untreated, it is usually fatal by the age of 2 or 3.[12][13] Treatment options are limited, but IPEX can be cured through a bone marrow transplant.[14]
The most representative criterion for the diagnosis of IPEX syndrome is autoimmune enteropathy. The first symptoms of enteropathy begin at birth and they are characterized by diarrhea, vomiting, gastritis, ileus, and colitis. The second hallmark is type 1 diabetes (T1D) and the worst complication of it is destruction of the pancreas, confirmed by histological examinations. Dermatitis is the next sign and it can be presented in three forms: eczematiform (mainly atopic dermatitis), ichthyosiform, psoriasiform, or combinations of them. Other skin manifestations can include cheilitis, onychodystrophy and alopecia. Other atypical symptoms include: thyroid and renal dysfunction, reduced counts of thrombocytes and neutrophils, arthritis, splenomegaly, lymphadenopathy and infections.[15]
The classical triad describes the three most common symptoms of IPEX syndrome: intractable diarrhea, type 1 diabetes (T1D), and eczema. These symptoms usually begin shortly after birth.
Other symptoms include: thyroid disease, kidney dysfunction, hematologic abnormalities, frequent infections, autoimmune hemolytic anemia, and food allergies, among others.[16]
Another common symptom of IPEX is enteropathy. This can present in many different ways, but the most common is intractable diarrhea. Vomiting and gastritis are also common. Other manifestations include Celiac disease and ulcerative colitis.[18]
The most common skin involvement is dermatitis. This may be eczematiform (mainly atopic dermatitis), ichthyosiform, psoriasiform, or a combination. Other skin manifestations include cheilitis, onychodystrophy, and alopecia.[19]
Dermatitis is the next sign and it can be presented in three forms: eczematiform (mainly atopic dermatitis), ichthyosiform, psoriasiform, or combinations of them. Other skin manifestations can include cheilitis, onychodystrophy and alopecia.
IPEX patients are usually born with normal weight and length at term. Nevertheless, the first symptoms may present in the first days of life,[20] and some reported cases labeled newborns with intrauterine growth retardation and evidence of meconium in the amniotic fluid.[21]
Mutations in FOXP3 gene causing IPEX syndrome - known in the year 2012.
IPEX syndrome is inherited in males through the FOXP3 gene in an x-linked recessive pattern. FOXP3's cytogenetic location is Xp11.23.[1][2] The FOXP3 gene has 12 exons and its full reading open frame encodes 431 amino acids. FOXP3 is a member of the FKH family of transcription factors and contains a proline‐rich (PRR) amino‐terminal domain, central zinc finger (ZF) and leucine zipper (LZ) domains important for protein–protein interactions. It also has a carboxyl‐terminal FKH domain required for nuclear localization and DNA‐binding activity. In humans, exons 2 and 7 are spliced and excluded from the protein.[15]
A large variety of mutations have been found, including single base substitutions, deletions, and splicing mutations.Data from 2018 describes over 70 mutations in FOXP3 gene leading to IPEX syndrome. This number has grown dramatically with new research.[22]For example, In 2010 there were only 20 mutations of FOXP3 known in the literature.[23] Some mutations, which cause FOXP3 expression to malfunction, lead to a defect in Treg production. Those patients do not have circulating CD4+/CD25+/FOXP3+ Treg cells. Reduced expression of FOXP3 has been described. These individuals may express normal levels of dysfunctional protein, which leads to mild symptoms later in life or during the neonatal period. Other individuals may have completely absent FOXP3 expression. In case of suspicion of IPEX syndrome patients should have genetic testing, even if FOXP31 T cells are present in the periphery.[24] A common location for mutation of FOXP3 leading to expression of malfunctioning protein is often localized in the DNA-binding domain called the forkhead domain. The mutation makes the truncated protein unable to bind its DNA binding site. This impairs its function concerning T regulatory lymphocytes development and functioning. The absence or dysfunction of regulatory T cells is the cause of autoimmune symptoms.[23]Data from 2018 describes over 70 mutations in FOXP3 gene leading to IPEX syndrome. Nonetheless, this number is still changing with new cases and discoveries coming.[22] For example, in 2010 there were only 20 mutations of FOXP3 known in the literature.[23]
FOXP3 can function as both a repressor and a trans‐activator of Treg cells depending on its interactions with other proteins. FOXP3 expression is characterised by controlling transcription, influencing epigenetic changes and post-transcriptional modifications. The N‐terminal repressor domain of FOXP3 can change transcription or epigenetic regulation of Treg cells. Transcriptional activity is altered through interactions between the N-terminal domain and Eos - which associates with CtBP1 and forms a corepressor complex. This complex binds the IL2 promoter and enables FOXP3 to repress IL2 transcription in Treg cells. FOXP3 forms complexes with histone deacetylase (HDAC)7, HDAC9, and the histone acetyl transferase TIP60, which alters epigenetic activity of Treg cells. The N‐terminal domain of FOXP3 can also antagonize the transcription factors RORγ and RORα, thereby inhibiting TH17 cell differentiation. FOXP3 is linked to TCR signaling by downstream transcription factors. All of these findings verify the importance of FOXP3 in the regulation of transcriptional activity/repression in Treg cells.[15]
This autoimmunity called IPEX is an attack from the body's own immune system against the body's own tissues and organs.[25] Early age onset of this disease in males causes severe enlargement of the secondary lymphoid organs, and insulin dependent diabetes[medical citation needed] This condition indicates the loss of CD4+CD25+ T regulatory cells, and express the transcription factor Foxp3. Foxp3 decrease is a consequence of unchecked T cell activation, which is secondary to loss of regulatory T cells.[26] Causes of death include haemorrhage, sepsis, Intractable diarrhoea and diabetic complications[5]
=== Early detection of the disease is crucial because mortality is on high level without treatment.[24] The diagnosis of immunodysregulation polyendocrinopathy enteropathy X-linked syndrome is consistent with the following criteria:[27][25]
In terms of treatment the following are done to manage the IPEX syndrome in those affected individuals (corticosteroids are the first treatment that is used):[25][28]
Individuals with IPEX will usually need supportive care in a hospital. Most common is nutritional treatment for enteropathy and insulin therapy for T1D. IPEX treatment tends to focus on managing symptoms, reducing autoimmunity, and/or treating secondary conditions. Usually, treatment will involve immunosuppression. Drugs used include:
Currently, the standard treatment for IPEX is a bone marrow transplant. If donor-recipient chimerism is achieved, individuals with IPEX can achieve complete remission.
In non-human research that has been conducted there is as well a special mouse model simulating the development and progression of the IPEX syndrome. The model mice are called "scurfy mice" and they have had 2 base pairs inserted within the Foxp3 gene. This leads to a frameshift mutation in Foxp3 gene and the expressed protein is truncated, causing functional deficiency of Treg cells. Consequently, autoreactive CD4+T cells and inflammatory cells are causing tissue damaging. Beside CD4+T cells to inflammation disorder contribute B cells by producing autoantibodies like antinuclear antibodies.[29] The mice had enlarged spleen and lymph nodes, redness in eyes, and skin abnormalities. The mice also had immunity problems and died after approximately 3 weeks.[22]
In 1982, Powel et al. published a case report of a family with 19 males who were affected by an X-linked syndrome with symptoms including polyendocrinopathy and diarrhea. The most common symptoms in this family were severe enteropathy, T1D, and dermatitis. Only 2 of the 19 affected males in the family survived past 3 years old. These individuals lived to 10 and 30 years old.[30] Powel's study is now widely considered the first documentation of IPEX.
Scurfy is a type of model mouse used for immunology research. They have had 2 base pairs inserted within the Foxp3 gene. This leads to a frameshift mutation in Foxp3 gene and the expressed protein is truncated, causing functional deficiency of Treg cells. Then, autoreactive CD4+T cells and inflammatory cells cause tissue damage.[29]Scurfy mice have an enlarged spleen and lymph nodes, squinted red eyes, and scaly or "ruffled" skin. The mice also have immunity problems and tend to die approximately 3 weeks after birth.[22] From 2000 - 2001, multiple studies confirmed that IPEX is the human equivalent of scurfy mice and that the FOXP3 gene is responsible.[31]
^ abcHannibal M, Torgerson T (1993-01-01). "IPEX Syndrome". In RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Ledbetter N, Mefford H (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID20301297.update 2011
